Title: The Role of MDM2 in FMRP regulation of neuronal development Fragile X Mental Retardation Protein (FMRP) is an RNA binding protein that binds to specific mRNAs to control their stability, localization, and protein translation. Loss of FMRP leads to Fragile X syndrome (FXS), the most common heritable cause of intellectual disability, and is also the greatest single-gene contributor to autism. Despite extensive effort, the mechanisms underlying the learning deficits in FXS are not fully understood and an effective therapy for this devastating disorder is lacking. Disappointing results from recent clinical trials underscore the pressing need for innovation in both target selection and cell type consideration. The development of an appropriate neural network is a prerequisite for normal brain functions. Although most neurons in the mammalian brain are born during embryonic neurogenesis, a significant amount of neuronal development continues postnatally. Neuronal maturation, including dendritic and axonal morphogenesis, spine development, synaptogenesis/pruning, and circuit integration, is critical for proper brain function and human health. In addition, new glutamatergic neurons are continuously produced in the dentate gyrus (DG) of the hippocampus, one of a few brain regions, possibly the only region in humans, with lifelong neurogenesis. Postnatal neurogenesis is important for cognitive outcomes and its impairment is implicated in both neuropsychiatric disorders and neurodegenerative diseases. Our lab has pioneered the investigation of FMRP in postnatal neurogenesis and our work has provided a causal link between postnatal neurogenesis and cognitive function in FXS, a postnatal developmental disorder. Using postnatal neurogenesis as a model system, we recently discovered that FMRP controls the levels of active (phosphorylated- or P-) MDM2. We were able to use a low dosage of Nutlin-3, an MDM2 inhibitor in clinical trials as a cancer treatment, to rescue cognitive deficits of adult FXS mice. Elevated MDM2 activity is found in a number of disease conditions, mostly cancers, and has been a focus for drug targeting. However, how elevated MDM2 impacts neurodevelopment and neuropsychiatric disorders is unclear. Our preliminary data show that FMRP-deficiency neurons also have elevated MDM2 levels and MDM2 inhibition rescue neuronal dendritic deficits of these neurons. Our exciting results have presented us with a set of lingering questions that are central to our understanding of FMRP regulation of neuronal development and developing novel treatment for FXS. This proposal aims to test the hypothesis that MDM2 is a key mediator of FMRP regulation of neurodevelopment. We will determine whether genetic reduction of MDM2 during postnatal development rescue certain behavioral deficits of FMRP-deficient mice (Aim 1), determine whether MDM2 dysregulation contributes to developmental deficits of FMRP-deficient neurons (Aim 2), and identify proteins and pathways that mediate MDM2 inhibition rescue of FMRP deficiency (Aim 3). The outcome of this study will yield important new information leading to novel therapeutic applications for FXS and potentially other neurodevelopmental disorders as well.